This invention relates to the use of certain 5-methyl-isoxazole-4-carboxylic acid anilides and 2-hydroxyethylidene-cyano acetic acid anilides in treating ocular diseases with immune etiology. The compounds are also useful to prolong graft survival of corneal or other ocular tissues and as surgical adjuncts in patients who are atopic or immune impaired.
The 5-methyl-isoxazole-4-carboxylic acid anilides are generically disclosed in U.S. Pat. No. 4,087,535, which patent is fully incorporated herein by reference to the extent it defines the 5-methyl-isoxazole-4-carboxylic acid anilides and their synthesis. The compound, 5-methylisoxazole-4-carboxylic acid-4-trifluoromethyl-anilide (leflunomide) which is encompassed within the generic class, is specifically disclosed in U.S. Pat. Nos. 4,284,786 and 4,351,841. The metabolite of leflunomide and the metabolites derivatives are described in U.S. Pat. No. 4,061,767 which is fully incorporated herein by reference to the extent it defines these compounds, which are 2-hydroxyethylidene-cyano acetic acid anilides, and their synthesis. Leflunomide's use as an antirheumatic, antiphlogistic, antipyretic, analgesic and as a compound for combating multiple sclerosis is also disclosed. In U.S. Pat. application No. 977,328 leflunomide and its metabolite, herein referred to as AL 3318, are disclosed for combatting chronic graft-versus-host and autoimmune diseases. Ocular indications and topical administration is not discussed.
Steroids and antimetabolite compounds, such as cyclophosphamide, have been used orally to treat severe uveitis, therapy is usually accompanied by the topical use of steroid therapy (ocular) to more rapidly control the inflammation. Steroids are also used in conjunction with antiviral, antiparasitic or antifungal agents to treat uveitis associated with microbial infections. Both antimetabolite and steroid therapies are general immunosuppressive treatments with ocular and systemic side effects.
Cyclosporin A (CsA), a fungal-derived immunosuppressive agent, has recently been used to treat dry eye (In dogs), severe uveitis, vernal conjunctivitis and to prevent corneal graft rejection in humans; see, for example, Nussenblatt et al., Survey of Ophthalmology, Vol.31, No.3 (November-December, 1986); and BenEzra et al., American Journal of Ophthalmology, Vol.101, p.298 (March, 986). CsA is effective, but has major side effects, including kidney damage and predilection for tumor formation. This makes long term therapeutic use, which is usually necessary, deleterious. In addition, due to its is size and structure, CsA is not water soluble and currently must be delivered in a suitable lipophilic formulation which is not optimal for topical ophthalmic use.